Whole Genome Sequencing Indicates Heterogeneity of Hyperostotic Disorders in Dogs.

Abstract

Craniomandibular osteopathy (CMO) and calvarial hyperostotic syndrome (CHS) are proliferative, non-neoplastic disorders affecting the skull bones in young dogs. Different forms of these hyperostotic disorders have been described in many dog breeds. However, an incompletely dominant causative variant for CMO affecting splicing ofhas been reported so far only in three Terrier breeds. The purpose of this study was to identify further possible causative genetic variants associated with CHS in an American Staffordshire Terrier, as well as CMO in seven affected dogs of different breeds. We investigated their whole-genome sequences (WGS) and filtered variants using 584 unrelated genomes, which revealed no variants shared across all affected dogs. However, filtering for private variants of each case separately yielded plausible dominantly inherited candidate variants in three of the eight cases. In an Australian Terrier, a heterozygous missense variant in thegene (c.1786G>A; p.(Val596Ile)) was discovered. A pathogenic missense variant inwas previously reported in humans with infantile cortical hyperostosis, or Caffey disease, resembling canine CMO. Furthermore, in a Basset Hound, a heterozygous most likely pathogenic splice site variant was found in(c.1446+1G>A), predicted to lead to exon skipping as shown before in-associated canine CMO of Terriers. Lastly, in a Weimaraner, a heterozygous frameshift variant in(c.1021_1024delTCAG; p.(Ser341ArgfsTer22)) might cause CMO due to the critical role ofin chondrogenesis and skeletal development. Our study indicates allelic and locus heterogeneity for canine CMO and illustrates the current possibilities and limitations of WGS-based precision medicine in dogs.